Populations of natural killer (NK) cells in human peripheral blood consists of hundreds of clones, each defined by a unique combination of KIR and CD94:NKG2 receptors. This diversity is proposed to increased the breadth and sensitivity of the NK cell response to infection, malignancy and transplanted bone marrow. Certain of the receptors engage polymorphic determinants of HLA class I molecules, developing inhibitory signals which enable NK cells to be self-tolerant. One such receptor, KIR3DL1, is specific for the one third of HLA-B allotype having the Bw4 epitopes. The expression of KIR3DLl, is specific for the one third of HLA-B allotypes having the Bw4 epitope. The expression of KIR3DLl, is specific for the one third of HLA-B allotypes having the Bw4 epitope. The expression of KIR3DLl by NK cells is fixed within an individual, but varies between individuals in a way that is genetically determined.. We hypothesize that patterns of KIR3DL1 expression are largely determined by genetic polymorphisms in the KIR gene family, with a lesser input from HLA polymorphisms. In Aim 1 this hypothesis will be tested by an analysis of sibling in which patterns of KIR3DLl will be correlated with KIR and HLA type. Whereas mice do not have KIR, this type of receptor is used by chimpanzee NK cells. However, the chimpanzee homologue of KIR3DL1 has a specificity for A and B allotypes that is quite distinct from the Bw4 specificity of human KIR3DLl. This difference between highly related species is consistent with adaptation of NK cell receptors to changes in pathogens. The changing specificity of KIR3DLl will be examined in Aim 2 by mutagenesis involving the twenty amino-acid substitutions that distinguish the human and chimpanzee KIR. The strategy will be to study the MHC class 1 specificity of mutant sin which domains, half-domains and single amino acids are replaced by those present in the other species. This investigation will determine the genetic factors that change the specificity of mutants in which domains, half-domains and single amino acids are replaced by those present in the other species. This investigation will determine the genetic factors that change the specificity and expression of a single NK-cell receptor. By focusing on the KIR3DLl receptor we hope to establish principles that will apply to other NK-cell receptors.